tbuckley/cabot-search huggingface dataset:
Efficacy and safety of Kras inhibitors in pancreatic cancer: A systematic review of clinical trials.
Authors: Sindhusha Veeraballi, Wajeeha Aiman, Amaar Ahmad, Navjot Grewal, Murad Qirem, Samer Jumean, Sahar Memar Montazerin, Muhammad Ashar Ali, Gunwant K. Guron, Hamid Salim Shaaban
Journal: Journal of Clinical Oncology (2023)

e16297 Background: Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive tumor and is one of the leading causes of cancer related deaths worldwide. Kirsten Rat Sarcoma (KRAS)mutation resulting in tumor cell proliferation and cancer progression is a frequently mutated oncogene in various cancers and is approximately seen in 90% of pancreatic ductal adenocarcinoma. Efforts are being done to target Kras mutation in the last 3–4 decades. Here in, we report the results of the systemic review of clinical trials done on chemotherapeutic agents targeting Kras mutated pancreatic cancer. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Clinicaltrials.gov, and Embase with mesh terms, “pancreatic neoplasm’’ and “kras” from the inception of data till 01/05/2023. We screened 4191 articles and included 3 clinical trials with published study results and 3 ongoing clinical trials. Results: In this systematic review, data on 2 chemotherapeutic agents Sotorasib (AMG510) and Adagrasib (MRTX849) which are Kras G12C inhibitors, are obtained from Code Break-100 and preliminary results of KRYSTAL-1 clinical trials, respectively. In these 2 clinical trials (N-48), all the patients had advanced pancreatic cancer with Kras G12C mutation and were previously treated with chemotherapy. 10 patients in Krystal-1 trial, who received adagrasib showed progression-free survival (PFS) of 6.6 months, disease control rate (DCR) of 100 % and partial response (PR) of 50%. 38 patients in the Code Break-100 trial, who received Sotorasib showed PFS of 4 months, DCR of 84.2% and PR of 21.1%. However, 50% of patients in the KRYSTAL-1 trial are still receiving treatment. Grade 3 /4 adverse events were seen in 21% and 16% of patients in the KRYSTAL-1 and Code Break-100 trial, respectively. Other Kras G12C inhibitors like D-1553, Sotorasib in combination with 2nd line chemotherapy are under investigation. Results of a clinical trial on anti KrasG12D siRNA done on locally advanced pancreatic cancer patients showed a median overall survival of 15.12 months with no dose limiting adverse events. A multinational randomized phase 2b clinical trial is ongoing for the evaluation of efficacy of siRNA based drug in combination with chemotherapy. Conclusions: Both Adagrasib and Sotorasib showed promising results in the pretreated Kras G12C pancreatic cancer patients with acceptable safety profile. Further exploration of these drugs and their combination with other chemotherapeutic agents is necessary. [Table: see text]
Gender and postoperative surgical margin status in MIBC: An analysis of the National Cancer Database.
Authors: Olivia French Gordon, Michael Joseph Whalen
Journal: Journal of Clinical Oncology (2023)

4599 Background: Women with muscle-invasive bladder cancer (MIBC) continue to experience persistent disparities in health outcomes despite accounting for less than 1/3 of newly diagnosed bladder cancer cases. Multiple studies have acknowledged the aggressive profile of female bladder cancer. This study aims to identify tangible areas to intervene and improve the delivery of oncologic care. Methods: The National Cancer Database (NCDB) was queried from 2004-2017 to conduct a retrospective cohort analysis of men and women with MIBC (cT2a-T4). N=41,037 patients with MIBC were reviewed, (30,313 male; 10,724 female). The primary endpoints were OS and surgical margin status. Logistic regression was performed to determine whether female sex conferred differential impact on surgical margin status when controlling for baseline clinical stage, age, receipt of neoadjuvant chemotherapy (NAC), Charleson-Deyo Comorbidity Classification (CDCC), and facility type. Cox proportional hazards assessed the impact of age, gender, margin status, CDCC and NAC on OS. Results: Logistic regression showed that sex, age, baseline clinical stage, CDCC, facility type and NAC were significant predictors of surgical margin status (p&lt;.001). Female sex was found to have a 14.4% higher probability of having positive residual margins (HR 1.144 (95% CI: 1.07-1.23), p&lt;.001). When adjusting for age, margin status, CDCC and NAC, Female gender (OS HR 1.063 (95% CI: 1.03-1.09), p&lt;.001), positive microscopic margins (OS HR 2.0 (95% CI: 1.90-2.10), p&lt;.001) and positive macroscopic margins (OS HR 2.62 (95% CI: 2.40-2.90), p&lt;.001) independently portended poorer OS and necessitated increased adjuvant XRT (p&lt;.001). Unexpected demographic findings included a significantly greater number of females than expected with a median household income &lt;$38,000 (p= 0.047) and a greater number of females in the upper quartile of patients without a HS diploma (p&lt;.001). The median days from diagnosis to definitive surgical treatment was significantly lower compared to males (58 vs 67 days; p&lt;.001). Conclusions: Women with MIBC faced obstacles to getting treatment (less education and lower median income). Despite these hurdles they may be more proactive with their health as seen by a shorter time from diagnosis to the surgical table. However, this proactivity has yet to pay off as women undergoing surgical treatment for MIBC were significantly less likely to have clear margins post-operatively. The urologic community must mirror female patient’s proactivity and further investigate the gender disparity in surgical treatment of MIBC. [Table: see text]
Machine learning-based multimodal prediction of prognosis in patients with resected intrahepatic cholangiocarcinoma.
Authors: Benoit Schmauch, Eliott Brion, Valérie Ducret, Naaz Nasar, Sarah McIntyre, Patrick Sin-Chan, Charles Maussion, William R. Jarnagin, Jayasree Chakraborty
Journal: Journal of Clinical Oncology (2023)

4121 Background: Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy and the second most common primary liver cancer. About a third of patients may benefit from surgery but recurrence is common and the overall survival is low. Accurate prognosis modeling that can predict response to treatment and outcome remains an unmet clinical need. Deep learning methods provide a new opportunity to better predict prognosis by extracting distinguishing characteristics interrogating multiple data sources, which appears to be superior to unimodal modeling. This study aimed to construct a predictive model of patient outcome and identify predictive biomarkers based on a combination of clinical, genomic, histological and radiological data. Methods: We analyzed 83 patients with iCCA that underwent surgery and designed a multi-modal model to predict overall survival (OS) and progression-free survival (PFS). Among these patients, each had one to three hematoxylin/eosin histology slides. As a pre-processing step, each histology slide was decomposed into patches, each patch was fed into a ResNet feature extractor to extract a feature representation of the patch, and the features across patches were aggregated with maximum pooling to yield a 2048-dimensional vector representation for each slide. Among these 83 patients, 76 patients had their tumors profiled for somatic genomic alterations using MSK-IMPACT, a deep targeted-sequencing assay. A binary matrix across altered genes and samples was created as an input to the prediction model. Cox proportional hazard models specific to each modality (clinical data, histological slides, and altered genes) were then designed and their predictions were averaged to produce the final log-risk score. The models were validated using a 5-fold, 5-repeat cross-validation with patient-level splits. Results: A model using only clinical and routine histological data achieved a concordance index of 0.74 (95% confidence interval, 0.64-0.82) for OS and 0.73 (0.64-0.78) for PFS. Adding information about genetic alterations improved performance for OS (0.80, 0.70-0.88) and similar performance for PFS (0.72, 0.64-0.79). Both models outperform a staging-based patient stratification. Conclusions: This study demonstrates that machine learning models can improve survival prediction using multi-modal data after resection of intrahepatic cholangiocarcinoma. Such models have the potential to improve risk stratification and treatment recommendations. [Table: see text]
Real world evidence on long-term survival of patients with endometrial cancer in Germany: Analysis of population-based cancer registry data on 49808 women.
Authors: Lukas Chinczewski, Dario Zocholl, Alexandra Wagner, Radoslav Chekerov, Elena Ioana Braicu, Jalid Sehouli
Journal: Journal of Clinical Oncology (2023)

e17623 Background: Endometrial cancer (EC) is the most common gynecological cancer worldwide. The understanding of clinicopathological characteristics has changed within the last years. Limited data are available regarding the long-term survival of EC patients. Methods: Clinical data and survival data for patients with EC diagnosed in Germany between 2010 and 2020 were gathered from the German national center for population-based cancer registry. Differentiated by histological subtype, 5- and 7-year survival rates were calculated. Results: 49,808 patients with newly diagnosed EC between 2010 and 2020 were included in the analysis. Median age at diagnosis was 68.1 years (IQR 59.0;76.4). 5-year and 7-year overall survival was 67.5% and 56.7%, respectively, and decreased with increasing FIGO-stage: 83.7% and 72.6% for FIGO IA, 71.0% and 56.3% for FIGO IB, 59.8% and 47.3% for FIGO II, 48.2% and 38.7% for FIGO IIIA , 32.5% and 20.7% for FIGO IIIB, 40.0% and 30.6% for FIGO IIIC, 13.3% and 8.2% for FIGO IVA, 16.4% and 13.9% for FIGO IVB, respectively. Regarding histological subtype, endometrioid carcinoma showed the best 5-year and 7-year overall survival rates with 72.5% and 61.3%, respectively, followed by clear cell carcinoma with 41.2% and 34.0%, serous carcinoma with 35.5% and 24.8%, and lastly carcinosarcoma with 28.5% and 23.0%. Of 3,765 patients with known cause of death, 53.8% were due to endometrial cancer. 19.0% died of cardiovascular disease and 18.8% of other malignancies. Conclusions: Our data represents deeper insight in the characterization of long-term survival patients of this tumor entity.
Preliminary safety, efficacy, and pharmacokinetics (PK) results of the EP4 antagonist INV-1120 from a phase I study in Chinese patients with advanced solid tumors.
Authors: Chang Liu, Miao Zhang, Jiajia Yuan, Dan Liu, Jifang Gong, Yi Zhu, Lishan Lin, Yongkui Sun, Johannes Nippgen, Lin Shen
Journal: Journal of Clinical Oncology (2023)

e14579 Background: INV-1120 is a highly selective, orally available inhibitor of PGE2-EP4, an immunosuppressive mediator in the TME. Objectives of this Phase I study in Chinese patients was to assess safety and pharmacokinetics and define a RP2D of INV-1120. Methods: Escalation was based on a 3+3 sequential design starting @ 60mg QD po as guided by the FIH trial in a Western population. DLT evaluation period was 4 weeks. Efficacy (RECIST 1.1) was evaluated every 8 weeks. Blood samples were collected for pharmacokinetics. Results: 9 patients were enrolled and treated with INV-1120 in 3 dose cohorts (60, 100, 150mg, n=3 each). All 9 patients had CRC. All 9 patients were evaluable for activity. Stable disease was observed in 3 of 9 (33.3%) patients. The median PFS (95% CI) was 55.0 days (range: 42.0-NE). The plasma exposure increased from 60 mg to 100 mg. Maximum concentrations were achieved approximately 2 hours post dose. The half-life was approximately 5-16 hours. No accumulation was noted after multiple doses. The PK profiles were similar to that in a Western population [NCT04443088, presented @ SITC 2022]. Conclusions: Single agent INV-1120 was generally well tolerated in the Chinese population and showed preliminary signs of antitumor activity in terms of stable disease. Data from this trial were in line with data in a Western population [NCT04443088, presented @ SITC 2022] and warrant further Global development. Due to the combined findings of this study and the above-mentioned sister study, the doses of 60, 100 and/or 150mg QD are proposed for further exploration in combination trials. Clinical trial information: ChiCTR20211872 . Clinical trial information: CTR20211872 . [Table: see text][Table: see text]
Treatment modalities of regorafenib and survival in metastatic colorectal (mCRC) patients: A real-world multicenter retrospective study.
Authors: Wang Qu, Zimin Liu, Liangjun Zhu, Xiaobing Chen, Bo Liu, Yun-Bo Zhao, Hao Yan, Xiujuan Qu, Shengmian Li, Ai-min Zang, Zhichao Jiang, Yongkun Sun, Ai-Ping Zhou
Journal: Journal of Clinical Oncology (2023)

e15571 Background: Regorafenib has been widely used as the later-line treatment for mCRC. This study aimed to describe the treatment modalities, as well as the efficacy and safety of regorafenib in a real-world setting. Methods: We conducted a retrospective study of patients (Pts) with refractory mCRC receiving at least one cycle of regorafenib as the third or higher line treatment from August 2017 to June 2020 in China. Demographic characteristics, treatment modality and survival were collected. The primary endpoint was overall survival. Uni- and multivariate analysis were conducted by Kaplan-Miere analysis and Cox regression model. Results: A total of 768 Pts from 10 centers were screened and 621 Pts were finally enrolled with a median age of 61 (18-84) years. 376 Pts received regorafenib monotherapy and 245 Pts accepted combination therapy. With a median follow-up time of 28.4 months, the median progression-free survival (mPFS) was 4.3 months (95%CI: 3.8-5.2) and the median overall survival (mOS) was 11.6 months (95% CI: 10.5-12.6). The mOS of Pts received regorafenib monotherapy (R, n = 376), regorafenib plus PD-1 inhibitor (R+I, n = 161), regorafenib plus chemotherapy (R+C, n = 53) and regorafenib plus chemotherapy, PD-1 inhibitor (R+C+I, n = 31) were 10.0, 13.2, 13.5 and 19.3 months, respectively (p = 0.0017). While the median PFS were 3.8, 5.4, 4.6 and 4.8 months, respectively (p = 0.4944). In multivariate analysis, treatment with R+I (HR = 0.712, 95%CI 0.521-0.973; p = 0.0330) and ECOG PS (HR = 0.400, 95%CI 0.232-0,690; p = 0.0010) were the only significant factors for superior mOS. Univariate analysis in subgroups demonstrated longer OS as well as PFS in KRAS mutated or antiangiogenesis therapy naïve Pts in R+I group than those in R group. Moreover, there was a tendency of shorter OS in Pts received 80mg as the final tolerated dose in R+I group compared to 160mg, while Pts received 120mg presented comparable survival. The incidence of all grade treatment-related adverse events was higher in R+I (87.9%) vs R (66.3%) group. Conclusions: The combination of regorafenib and PD-1 inhibitor was commonly adopted as the later-line treatment in mCRC patients in real-world practice and seemed to have a prolonged overall survival than regorafenib alone. Further confirmatory studies are warranted. Clinical trial information: NCT04835324 .
Final results from TACTI-002 Part C: A phase II study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in patients with metastatic 2nd line head and neck squamous cell carcinoma unselected for PD-L1.
Authors: Bernard Doger de Spéville, Enriqueta Felip, Martin Forster, Margarita Majem, Pawan Bajaj, Julio Antonio Peguero, Enric Carcereny, Matthew G Krebs, Uma Mukherjee, Christian Mueller, Frederic Triebel
Journal: Journal of Clinical Oncology (2023)

6029 Background: Eftilagimod alpha (E), a soluble LAG-3 protein, acts as an MHC class II agonist triggering activation of antigen-presenting cells (APC) and CD8 T-cells. Using efti to enhance patients’ immunity may lead to stronger anti-tumor responses than observed with pembrolizumab (P) alone. We report final results from Part C of the TACTI-002 trial (NCT03625323) where 2 nd line metastatic head and neck squamous cell carcinoma (HNSCC) patients (pts) unselected for PD-L1 were treated with E + P. Methods: Pts with metastatic HNSCC, unselected for PD-L1 expression with disease progression on or after 1 st line platinum-based therapy (± cetuximab) were enrolled. Primary endpoint (EP) was objective response rate (ORR) by iRECIST. Other EPs included tolerability, progression free survival (PFS), duration of response (DoR), and overall survival (OS). Pts received E (30 mg SC Q2W for eight 3-week cycles and then Q3W up to 1 yr) with P (200 mg IV Q3W up to 2 yrs). Imaging was performed Q9W. PD-L1 was retrospectively assessed using the IHC 22C3 kit. The study was approved by ethic committees and institutional review boards. Results: 39 pts were enrolled between Mar 2019-Jan 2021 (cut-off Jul 2022) with HNSCC of oropharynx (38%), oral cavity (32%), hypopharynx (19%) and larynx (16%). Median age was 63 yrs (48-84 yrs) and 90% were male. ECOG PS was 0 and 1 in 35% and 65% of pts. Two pts were excluded from efficacy results due to fatal COVID-19 prior to their first post-baseline scan. The primary EP, ORR by iRECIST, was 30% with 14% complete responders (see table). ORR by RECIST 1.1 was comparable (24%). Median PFS by iRECIST was 2.1 mo with 32% of pts progression-free at 6 mo. Median OS was 8.7 mo with 46% alive at 12 mo. Median DoR by iRECIST was not reached with 17 mo min FU. Responses were seen in all PD-L1 subgroups (see table). ORR, 6-mo PFS, 12-mo OS rates for PD-L1 CPS ≥20 were 60%, 53%, 73% with a median OS of 15.5 months. Two pts (5%) discontinued due to adverse events (AE) (fatigue and arthralgia [each grade 2]; pneumonitis [grade 3]) that were related to study treatment (efti and/or pembro). The most common (≥15%) AEs were hypothyroidism (21%), asthenia (21%), cough (18%), anemia (18%), weight decrease (18%), and fatigue (15%). Conclusions: Efti + pembrolizumab is safe, showing encouraging antitumor activity in platinum and partially cetuximab pre-treated, 2nd line HNSCC patients. TACTI-003 (NCT04811027) a randomized study in 1st line HNSCC is currently recruiting. Response by iRECIST: Clinical trial information: NCT03625323 . [Table: see text]
18F-FDG PET and CT identifiers of high-risk lesions in the stomach and esophagus.
Authors: Ashkan EighaeiSedeh, Bashar Kako, Caitlin Deffler, Thomas Ng, Onofrio Antonio Catalano, Umar Mahmood, Pedram Heidari, Shadi Abdar Esfahani
Journal: Journal of Clinical Oncology (2023)

e16036 Background: Assessing the significance of incidentally found increased 18F-FDG uptake in the stomach and esophagus on PET/CT has long been a challenge. Currently, there is no clear guideline to assist clinicians with distinguishing malignant from benign uptake. This study aims to compare various PET and CT characteristics used separately and collectively, to identify high-risk foci of uptake. Methods: 18F-FDG PET/CT images from August 2018 to October 2022 were reviewed and patients who completed a follow up EGD due to incidentally found increased gastroesophageal uptake were included in this study. To identify high-risk foci, the following PET and CT characteristics were used: 1) uptake intensity, using lesion SUVmax relative to mediastinal blood pool and liver SUVmean values (≤ blood pool = 0, &gt; blood pool but &lt; liver = 1, ≥ liver = 2); 2) uptake pattern (diffuse = 0, segmental = 1, focal = 2); 3) eccentricity (circumferential= 0, eccentric = 1); and CT correlation score (normal = 0, thickening = 1, mass = 2). Cut-off values were determined using receiver operating characteristic (ROC) curves. Benign and malignant uptake were compared to histological findings using Pearson’s chi-square test. Results: Incidental uptake in the stomach and/or esophagus were noted in 473/7805 (6.1%) patients of which 89 (18.8%) had a follow up EGD and were included in this study. Uptake intensity did not differentiate benign and malignant as SUVmax was greater than background tissues in all cases (Score =2). Uptake pattern, eccentricity, and CT-correlation of PET were significantly different between benign and malignant foci ( p &lt; 0.001, p &lt; 0.001, and p &lt; 0.001, Chi-square). Using cut-off scores from ROC curves, the predictive value of different PET/CT characteristics in identifying high-risk foci was reviewed. Conclusions: PET eccentricity along with anatomic CT correlative findings, offer similar value in predicting high-risk uptake foci to uptake pattern, eccentricity, and CT correlation combined. These are both, however, superior to other PET/CT characteristics used alone or in combination. [Table: see text]
Investigation of synthetic lethality gene pairs in the DNA damage response pathway in response to immunotherapy in pan-cancer.
Authors: Hongyan Huang, Miao Liu, Ding Zhang
Journal: Journal of Clinical Oncology (2023)

2567 Background: The concept of synthetic lethality (SL) refers to the phenomenon where the simultaneous loss of function of two genes leads to cell death, while the loss of function of either gene alone has no effect. PARP inhibitors target poly ADP ribose polymerase (PARP) enzymes, which are involved in DNA repair, are the successful cases of utilizing synthetic lethality-based therapy to treat cancers with DNA damage response (DDR) deficiency. The prognosis for cancer patients already has a combination of synthetic lethal mutations especially in DDR pathway can vary and it is not yet fully understood how these mutations may impact the response to immunotherapy. Methods: SL gene combinations in the DDR pathway were screened out from SynLethDB database (http://histone.sce.ntu.edu.sg/SynLethDB/). The immunotherapy cohort (Samstein 2019, n=1661) and non-immunotherapy cohort (Zehir 2017, n=10336) with solid tumor were used to Kaplan-Meier analyze the correlation between SL gene combinations and prognosis. TMB scores were compared between DDR co-mutation group and non DDR co-mutation group. For investigating the associations between immune infiltrates and genetic features, TIMER 2.0 database ( http://timer.cistrome.org/ ) was conducted to estimation of immune infiltration levels on DDR mutation genes in pan-cancer. Results: 430 pairs of DDR mutation combinations were used to subgroup stratification, the DDR co-mutation group was associated with worse prognosis in non-immunotherapy cohort (HR=1.305, p&lt;0.0001) but better in immunotherapy cohort (HR=0.741,p&lt;0.0061). Interestingly, the TMB score in the DDR co-mutation group was significantly higher than non DDR co-mutation group (mean 50.03 vs 8.868, p&lt;0.0001) in immunotherapy cohort. The high-frequency mutation combinations (&gt;10%) were ATM-POLE(14.40%), ATM-ATR (13.60%), ATR-BRCA2 (13.60%), ATM-BRCA2 (12.00%) and BRCA2-RECQL4 (10.40%), respectively. Comparing common immune component with statistically significant under different DDR mutant genes, the ATM-POLE co-mutation tumor tended to have more CD4+ T cell infiltration while the ATM-ATR co-mutation tumor appeared to have more myeloid dendritic cell infiltration. Conclusions: The combinations of DDR SL mutation tumor might result to worse prognosis whereas these patients might benefit from immunotherapy. Our results will help to shed light on the complex interplay for the combinations of SL mutation in DDR pathway between cancer cells and the immune system and provide new insights into the development of effective cancer treatments.